Epidemiological data support a causal link between exposure to elevated levels of particulate matter (PM) and increased lower respiratory tract infections (LRTIs) in children. During the H1N1 influenza (Flu) pandemic, exposure to PM was a potential contributing factor to the disparity in the increased levels of H1N1-induced morbidity and mortality observed in Mexico and the United States. Interestingly, the risk of LRTIs due to PM exposure is highest in infants. Despite strong evidence associating PM exposure and LRTI susceptibility, morbidity, and mortality in infants; there is very little research on this subject nd the mechanisms underlying this phenomenon are unknown. We have developed a novel neonatal (<7 d of age) rodent model for studying PM exposures, which we apply here to understand the effects of PM on enhanced susceptibility to LRTI and LRTI-mediated disease severity. Our data show that age of exposure to PM is important in predicting LRTI disease sequela and that infant exposure to PM initiated several events that may explain the epidemiological data. First, exposure of neonatal mice to PM results in epithelial disruption, which allows for enhanced access of respiratory viruses to the lower airways. Second, adaptive immune responses following PM exposure in neonates are suppressive in nature (i.e. increased IL10 and Treg cells and decreased Th1, Tc1, and Th17 cell numbers) and not protective. The end result is enhanced severity of Flu-mediated disease as evidenced by increased pulmonary viral loads and mortality in neonatal mice infected following exposure to PM. Our data further suggest that epithelial signals either cell associated or secreted (i.e. epimmunome) are used to direct this aberrant immune response to Flu. Thus, we hypothesize that exposure to PM during infancy increases the risk for and severity of infectious respiratory disease through a process involving epithelial disruption and alteration of the epimmunome. Our specific aims will address the following important questions. 1) How does neonatal exposure to PM increase susceptibility to Flu infection and enhanced disease? 2) Is epithelial disruption following neonatal exposure to PM responsible for enhanced Flu susceptibility? 3) Does neonatal exposure to PM enhance Flu susceptibility by suppressing the pulmonary immune response? Completion of these studies will provide us with an understanding of the molecular signaling events between injured epithelial cells and DCs crucial to understand Flu pathogenesis in PM exposed infants and to identify pharmacologic targets for the treatment of environmentally-induced asthma exacerbations due to LRTI.